Introduction
Deficient endogenous production of NO has been hypothesized to play a role in the development of clinical hypertension. We have provided an important proof of this concept, by showing that pharmacological NO synthase inhibition with nitro-L-arginine methyl ester (L-NAME) raises blood pressure into the hypertensive range, in otherwise normotensive humans (Sander et al. 1999). The aim of the present study was to further probe the time-course and underlying mechanisms of this new model of acute human hypertension. Specifically, we tested the extent to which the L-NAME-induced increases in blood pressure were sympathetically mediated.
Methods
In healthy young adults (n=10), mean arterial pressure (MAP), heart rate and muscle sympathetic nerve activity by microneurography of the peroneal nerve (SNA) were measured before, during and for 2 hours after L-NAME (4 mg/kg intravenously over 1 hour) and during 3 hours of continuous dose-adjusted phenylephrine (PE). In an additional protocol (n=7), we determined the effects on MAP induced by the alpha-adrenergic receptor antagonist, phentolamine (0,2 mg/kg over 12 minutes) when administered 90 minutes after the end of L-NAME or D-NAME, an inactive control for L-NAME, or during a continuous infusion of angiotensin-II (A-II), which has been hypothesized to cause a hypertensive response partly sympathetically mediated. The dose of A-II was also adjusted to mimic the pressor response induced by L-NAME.
Results
L-NAME and PE caused robust increases in MAP of matched magnitudes (+23±4 vs. 25±5 mmHg) and time-courses (maximum during the third hour). Baseline SNA, scored blindly, were identical (19±3 vs. 19±4 bursts/min), and initially declined to similar values (9±2 vs. 10±2 bursts/min after 90 min). The major new finding is, that during the late progressive blood pressure increases, SNA was consistently higher after L-NAME vs. PE (12±3 vs. 7±1 bursts/min after 3 hours, p<0.05). Heart rate responses were not significantly different between L-NAME and PE. Subsequent administration of L-arginine (200 mg/kg) caused substantial reversal of the L-NAME-effects, but not the PE-effects. In the additional protocol the matched hypertensive responses observed during the third hour of L-NAME and continuous dose-adjusted A-II were both partly reversed by alpha-adrenergic receptor blockade with phentolamine (41±5 vs. 26±3 % reversal, p=0.06). In contrast, phentolamine did not lower blood pressure after D-NAME.
Conclusions
These data provide preliminary direct microneurographic and indirect supportive evidence that the late progressive L-NAME-induced increase in blood pressure is at least partly sympathetically mediated. This finding supports the concept that neuronally produced nitric oxide is involved in the central control of sympathetic outflow from the brainstem.
References
Sander M, Chavoshan B & Victor RG. 1999 Hypertension 33:937-42.